Method of deuteration

ABSTRACT

The present invention relates to a method for deuteration of a compound represented by the general formula [1]: 
 
R 1 —X—R 2   [1]
         wherein, R 1  represents an alkyl group or an aralkyl group, which may have a carbon-carbon double bond and/or triple bond; R 2  represents an alkyl group which may have a carbon-carbon double bond and/or triple bond, an aryl group, an aralkyl group, an alkoxy group, an aryloxy group or a hydroxyl group; X represents a carbonyl group or a hydroxylmethylene group, R 1  and R 2  may form an alicyclic ring together with a carbon atom contained in X; provided that R 2  represents an alkyl group which may have a carbon-carbon double bond and/or triple bond, an aryl group or an aralkyl group when X is a hydroxylmethylene group, comprising reacting the compound represented by the general formula [1] with a heavy hydrogen source in the co-presence of an activated catalyst selected from a palladium catalyst, a platinum catalyst, a rhodium catalyst, a ruthenium catalyst, a nickel catalyst and a cobalt catalyst. The method of the present invention can significantly improve working environment because the deuteration, which has been conventionally carried out under severe conditions such as basic condition, can be carried out under neutral condition. Further, even when the compound represented by the general formula [1] is one having a carbon-carbon double bond or triple bond, the method for deuteration of the present invention enables to efficiently carry out objective deuteration without reduction of said double bond or triple bond.

TECHNICAL FIELD

The present invention relates to a method for deuteration of a compound,using an activated catalyst.

BACKGROUND OF THE INVENTION

A compound having a heavy hydrogen (deuterium and tritium) is said to beuseful in various purposes. For example, a deuterated compound is veryuseful in clarification of reaction mechanism and substance metabolismand used widely as a labeled compound. Said compound is also known to beuseful as drugs, pesticides, organic EL materials, and the like due tochange in stability and property itself by isotope effect thereof. Acompound having tritium is also said to be useful as a labeled compoundin animal tests and the like to survey absorption, distribution,concentration in blood, excretion, metabolism and the like of drugs,etc. Therefore, research on a compound having a heavy hydrogen(deuterium and tritium) has been increasing also in these fields.

Various methods for obtaining these compounds having a heavy hydrogenhave conventionally been used, however, among others, there were manyproblems to be solved in deuteration technology of a compound having acarbonyl group or a hydroxyl group, and it was difficult to efficientlyand industrially obtain a deuterated compound.

Conventional technology includes, for example, 1) a method fordeuteration of a carboxylic acid under basic condition using heavyhydrogen peroxide (see U.S. Pat. No. 3,849,458), 2) a method fordeuteration of an alcohol or a carboxylic acid using an iridium complexas a catalyst and heavy water as a heavy hydrogen source (see J. Am.Chem. Soc. Vol. 124, No. 10, 2092 (2002)), 3) a method for deuterationof a fatty acid using a palladium carbon as a catalyst and only heavyhydrogen gas as a heavy hydrogen source (see LIPIDS, Vol. 9, No. 11, 913(1974), 4) a method for deuteration of acrylic acid, methyl acrylate,methacrylic acid or methyl methacrylate using a metal selected from themetals belonging to the 8th group metals as a catalyst and heavy wateror heavy water+heavy hydrogen gas as a heavy hydrogen source (seeJP-B-5-19536, JP-A-61-277648 and JP-A-61-275241) and 5) a method fordeuteration of acrylic acid, methyl methacrylate, and the like using acatalyst not activated with hydrogen and heavy water as a heavy hydrogensource (see JP-A-63-198638).

However, each of these methods has problems as described below.

1) A method for deuteration of a carboxylic acid under basic conditionusing heavy hydrogen peroxide has a problem that this method cannotdeuterate a compound labile to decomposition by heavy hydrogen peroxideor under basic condition, and further, complicated purificationprocesses are required in isolation of thus deuterated compound, becausereaction solution is not neutral, even if a compound not labile todecomposition under acidic or basic condition is used as a substrate.

2) A method for deuteration of an alcohol compound or a carboxylic acidusing an iridium complex as a catalyst and heavy water as a heavyhydrogen source has a problem that deuteration ratio of a hydrogen atombecomes higher as the hydrogen atom is located at a more distantposition from the carbon atom to which a hydroxyl group in an alcoholcompound is bonded, and deuteration ratio of the hydrogen atom near thehydroxyl group becomes extremely low. Furthermore, an iridium complex tobe used as a catalyst is difficult to manufacture or purchase becausethe compound itself is unstable.

3) A method for deuteration of a fatty acid using a palladium carbon asa catalyst and heavy hydrogen gas generated by electrolysis of KOD+D₂Oas a heavy hydrogen source is not adequate for practical use due torequirement of a special apparatus for production of heavy hydrogen gasand very complicated operation thereof. Further, such a method usingheavy hydrogen gas as a heavy hydrogen source can hardly deuterate acompound such as an unsaturated fatty acid having an unsaturated bond,which is reduced by hydrogenation.

4) A method for deuteration of acrylic acid, methyl acrylate,methacrylic acid or methyl methacrylate using a metal selected from themetals belonging to the 8th group metals as a catalyst and heavy wateror heavy water+heavy hydrogen gas as a heavy hydrogen source has thefollowing problems. Namely, when only heavy water is used as a heavyhydrogen source, deuteration ratio is low because a non-activatedcatalyst is used. On the other hand, when heavy water+heavy hydrogen gasare used as a heavy hydrogen source, hydrogenation (catalytic reduction)of a carbon-carbon double bond moiety of acrylic acid, methyl acrylate,methacrylic acid or methyl methacrylate as a reactive substrate easilyoccurs with heavy hydrogen gas as well as deuteration, and it isimpossible to deuterate the compound leaving said bond unchanged.

5) A method for deuteration of acrylic acid or methyl methacrylate usinga catalyst not activated with hydrogen and heavy water as a heavyhydrogen source has a problem of low deuteration ratio due to use of anon-activated catalyst as a catalyst.

In view of the above situation, development of a method is needed fordeuteration of a carbonyl compound or a secondary alcohol compoundefficiently and industrially irrespective of kinds of a substituent andpresence or non-presence of a double bond and a triple bond.

SUMMARY OF THE INVENTION

The present invention relates to a method for deuteration of a compoundrepresented by the general formula [1]:R¹—X—R²  [1]

wherein, R¹ represents an alkyl group or an aralkyl group, which mayhave a carbon-carbon double bond and/or a triple bond; R² represents analkyl group which may have a carbon-carbon double bond and/or a triplebond, an aryl group, an aralkyl group, an alkoxy group, an aryloxy groupor a hydroxyl group; X represents a carbonyl group or ahydroxylmethylene group; R¹ and R² may form an alicyclic ring togetherwith a carbon atom contained in X; provided that R² represents an alkylgroup which may have a carbon-carbon double bond and/or a triple bondwhen X is a hydroxylmethylene group, an aryl group or an aralkyl group,

which comprising reacting the compound represented by the generalformula [1] with a heavy hydrogen source in the co-presence of anactivated catalyst selected from a palladium catalyst, a platinumcatalyst, a rhodium catalyst, a ruthenium catalyst, a nickel catalystand a cobalt catalyst.

Further, the present invention also relates to a deuteratedtricyclo[5.2.1.0^(2,6)]decan-8-ol wherein a deuteration ratio thereof is60% or more.

BEST MODE FOR CARRYING OUT THE INVENTION

In a present invention, a heavy hydrogen means deuterium (D) and tritium(T) and deuteration means substitution with deuterium and tritium.Further, in the present specification, deuteration ratio means a ratioof an amount of hydrogen atoms substituted by heavy hydrogen atom to thetotal amount of hydrogen atoms in a compound represented by the generalformula [1].

In a method for deuteration of the present invention, the alkyl group ofan alkyl group which may have a carbon-carbon double bond and/or triplebond, represented by R¹ and R² of a compound represented by the generalformula [1] may be straight chained, branched or cyclic, and includesone generally having 1 to 20, preferably 1 to 15, more preferably 1 to10 and further more preferably 1 to 6 carbon atoms, which isspecifically exemplified by, for example, a methyl group, an ethylgroup, a n-propyl group, an isopropyl group, a n-butyl group, anisobutyl group, a sec-butyl group, a tert-butyl group, a n-pentyl group,an isopentyl group, a sec-pentyl group, a tert-pentyl group, a neopentylgroup, a n-hexyl group, an isohexyl group, a 3-methylpentyl group, a2-methylpentyl group, a 1,2-dimethylbutyl group, a n-heptyl group, anisoheptyl group, a sec-heptyl group, a n-octyl group, an isooctyl group,a sec-octyl group, a n-nonyl group, a n-decyl group, a n-undecyl group,a n-dodecyl group, a n-tridecyl group, a n-tetradecyl group, an-pentadecyl group, a n-hexadecyl group, a n-heptadecyl group, an-octadecyl group, a n-nonadecyl group, a n-icosyl group, a cyclopropylgroup, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, acyclooctyl group, a cyclononyl group, a cyclodecyl group, a cycloundecylgroup, a cyclododecyl group, a cyclotridecyl group, a cyclotetradecylgroup, a cyclopentadecyl group, a cyclohexadecyl group, acycloheptadecyl group, a cyclooctadecyl group, a cyclononadecyl groupand a cycloicosyl group.

The alkyl group having a carbon-carbon double bond or triple bondincludes one containing at least one double bond or triple bond in achain of an alkyl group having not less than 2 carbon atoms among theabove alkyl groups, and the alkyl group having a carbon-carbon doublebond and triple bond includes one containing each at least one doublebond and triple bond, in a chain of an alkyl group having not less than4 carbon atoms among the above alkyl groups, and the specific examplesof an alkyl group having such a carbon-carbon double bond and/or atriple bond include, for example, alkyl groups having only acarbon-carbon double bond such as a vinyl group, an allyl group, a1-propenyl group, an isopropenyl group, a 3-butenyl group, a 2-butenylgroup, a 1-butenyl group, a 1,3-butadienyl group, a 4-pentenyl group, a3-pentenyl group, a 2-pentenyl group, a 1-pentenyl group, a1,3-pentadienyl group, a 2,4-pentadienyl group, a1,1-dimethyl-2-propenyl group, a 1-ethyl-2-propenyl group, a1,2-dimethyl-1-propenyl group, a 1-methyl-1-butenyl group, a 5-hexenylgroup, a 4-hexenyl group, a 2-hexenyl group, a 1-hexenyl group, a1-methyl-1-hexenyl group, a 2-methyl-2-hexenyl group, a3-methyl-1,3-hexadienyl group, a 1-heptenyl group, a 2-octenyl group, a3-nonenyl group, a 4-decenyl group, a 1-dodecenyl group, a1-tetradecenyl group, a 1-hexadecenyl group, a 1-octadecenyl group, a1-icosenyl group, a 1-cyclopropenyl group, a 2-cyclopentenyl group, a2,4-cyclopentadienyl group, a 1-cyclohexenyl group, a 2-cyclohexenylgroup, a 3-cyclohexenyl group, a 2-cycloheptenyl group, a 2-cyclononenylgroup, a 3-cyclodecenyl group, a 2-cyclotridecenyl group, a1-cyclohexadecenyl group, a 1-cyclooctadecenyl group and a1-cycloicosenyl group; alkyl groups having only a carbon-carbon triplebond such as an ethynyl group, a 2-propynyl group, a 1-propynyl group, a2-pentynyl group, a 2-nonyl-3-butynyl group, a cyclohexyl-3-ynyl group,a 4-octynyl group and a 1-methyldecyl-5-ynyl group; alkyl groups havingboth of a carbon-carbon double bond and triple bond such as a1-buten-3-ynyl group, a 2-penten-4-ynyl group, a5-(3-pentenyl)-3,6,8-decatrien-1-ynyl group, a6-(1,3-pentadienyl)-2,4,7-dodecatrien-9-ynyl group and a6-(1-penten-3-ynyl)-2,4,7,9-undecatetraenyl group.

The aralkyl group represented by R¹ and R² may be straight chained,branched or cyclic, and includes the above alkyl groups substituted withthe above aryl groups, one having generally 7 to 34, preferably 7 to 20and more preferably 7 to 15 carbon atoms, which is specificallyexemplified by, for example, a benzyl group, a phenylethyl group, aphenylpropyl group, a phenylbutyl group, a phenylpentyl group, aphenylhexyl group, a phenylheptyl group, a phenyloctyl group, aphenylnonyl group, a phenyldecyl group, a phenylundecyl group, aphenyldodecyl group, a phenyltridecyl group, a phenyltetradecyl group, aphenylpentadecyl group, a phenylhexadecyl group, a phenylheptadecylgroup, a phenyloctadecyl group, a phenylnonadecyl group, a phenylicosylgroup, a naphthylethyl group, a naphthylpropyl group, a naphthylbutylgroup, a naphthylpentyl group, a naphthylhexyl group, a naphthylheptylgroup, a naphthyloctyl group, a naphthylnonyl group, a naphthyldecylgroup, a naphthylundecyl group, a naphthyldodecyl group, anaphthyltridecyl group, a naphthyltetradecyl group, a naphthylpentadecylgroup, a naphthylhexadecyl group, a naphthylheptadecyl group, anaphthyloctadecyl group, a naphthylnonadecyl group, a naphthylicosylgroup, an anthrylethyl group, an anthrylpropyl group, an anthrylbutylgroup, an anthrylpentyl group, an anthrylhexyl group, an anthrylheptylgroup, an anthryloctyl group, an anthrylnonyl group, an anthryldecylgroup, an anthrylundecyl group, an anthryldodecyl group, ananthryltridecyl group, an anthryltetradecyl group; an anthrylpentadecylgroup, an anthrylhexadecyl group, an anthrylheptadecyl group, ananthryloctadecyl group, an anthrylnonadecyl group, an anthrylicosylgroup, a phenanthrylethyl group, a phenanthrylpropyl group, aphenanthrylbutyl group, a phenanthrylpentyl group, a phenanthrylhexylgroup, a phenanthrylheptyl group, a phenanthryloctyl group, aphenanthrylnonyl group, a phenanthryldecyl group, a phenanthrylundecylgroup, a phenanthryldodecyl group, a phenanthryltridecyl group, aphenanthryltetradecyl group, a phenanthrylpentadecyl group, aphenanthrylhexadecyl group, a phenanthrylheptadecyl group, aphenanthryloctadecyl group, a phenanthrylnonadecyl group and aphenanthrylicosyl group.

The aryl group represented by R² includes one generally having 6 to 14,preferably 6 to 10 carbon atoms, which is specifically exemplified by,for example, a phenyl group, a naphthyl group and an anthryl group.

The alkoxy group represented by R² may be straight chained, branched orcyclic, and includes one generally having 1 to 20, preferably 1 to 15,more preferably 1 to 10 and further more preferably 1 to 6 carbon atoms,which is specifically exemplified by, for example, a methoxy group, anethoxy group, a propoxy group, an isopropoxy group, a butoxy group, anisobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxygroup, a neopentyloxy group, a hexyloxy group, an isohexyloxy group, atert-hexyloxy group, a heptyloxy group, an octyloxy group, a nonyloxygroup, a decyloxy group, an undecyloxy group, a tetradecyloxy group, ahexadecyloxy group, a heptadecyloxy group, a nonadecyloxy group, anicosyloxy group, a cyclohexyloxy group, a cyclooctyloxy group, acyclodecyloxy group and a cyclononadecyloxy group.

The aryloxy group represented by R² includes one generally having 6 to14, preferably 6 to 10 carbon atoms, which is specifically exemplifiedby a phenoxy group, a naphthyloxy group and an anthryloxy group.

The hydroxyl group represented by R² also includes one, wherein thehydrogen atom thereof is replaced by an alkali metal atom such assodium, potassium and lithium.

The alicyclic ring, which is formed by R¹ and R² together with a carbonatom contained in X, may be a monocyclic ring or a polycyclic ring, andincludes one having generally 3 to 15, preferably 5 to 10, morepreferably 6 to 8 carbon atoms, which is specifically exemplified by,for example, a saturated monocyclic ring such as a cyclopropane ring, acyclobutane ring, a cyclopentane ring, a cyclohexane ring, acycloheptane ring, a cyclooctane ring, a cyclononane ring, a cyclodecanering, a cycloundecane ring, a cyclododecane ring, a cyclotridecane ring,a cyclotetradecane ring and a cyclopentadecane ring; an unsaturatedmonocyclic ring such as a cyclobutenyl ring, a cyclopentenyl group, acyclohexenyl group, a cycloheptenyl group, a cyclooctenyl group and acyclononenyl group; a saturated or unsaturated polycyclic ring such as atricyclodecane ring, a dicyclopentadiene group, a perhydronaphthalenering, a perhydroanthracene ring, a norbornane ring, norpinane ring, anorcarane ring and an adamantane ring.

In the compound represented by the general formula [1] of the presentinvention, the alkyl group and the aralkyl group, which may have acarbon-carbon double bond and/or triple bond, represented by R¹ and R²,and the aryl group, the alkoxy group and the aryloxy group, representedby R² may further have generally 1 to 5, preferably 1 to 3 varioussubstituents. The substituent includes, for example, an alkyl group, anaryl group, an aralkyl group, an alkoxy group, an aryloxy group, analkoxycarbonyl group, an aryloxycarbonyl group, an acyl group, acarboxyl group, an aldehyde group, a hydroxyl group, an amino group, anaminoalkyl group, a cyano group, a carbamoyl group and an alkylcarbamoylgroup, which may have a carbon-carbon double bond and/or triple bond.

Specific examples of the alkyl group, the aralkyl group, the aryl group,the alkoxy group, the aryloxy group, which may have a carbon-carbondouble bond and/or a triple bond and the hydroxyl group, as the abovesubstituent of the group represented by R¹ and/or R² include the sameone as those represented by R¹ and/or R².

Further, specific examples of the alkoxycarbonyl group and thearyloxycarbonyl group as the substituent of the group represented by R¹and/or R² include one, wherein a carbonyl group is bonded to the oxygenatom of the above specific examples of the alkoxy group and the arylgroup represented by R¹ and/or R².

The acyl group as a substituent of the group represented by R¹ and/or R²includes one having generally 2 to 20, preferably 2 to 10, morepreferably 2 to 4 carbon atoms, which is specifically exemplified by,for example, an acyl group derived from saturated aliphaticmonocarboxylic acids such as an acetyl group, a propionyl group, abutyryl group, an isobutyryl group, a valeryl group, an isovalerylgroup, a pivaloyl group, a lauroyl group, a myristoyl group, a palmitoylgroup and a stearoyl group; an acyl group derived from unsaturatedaliphatic monocarboxylic acids such as an acryloyl group, a propioloylgroup, a methacryoyl group, a crotonoyl group and an oleoyl group; anacyl group derived from aromatic monocarboxylic acids such as a benzoylgroup and a naphthoyl group.

The carboxyl group as a substituent of the group represented by R¹and/or R² also includes one, wherein the hydrogen atom thereof isreplaced by an alkali metal atom such as sodium, potassium and lithium.

The amino group as a substituent of the group represented by R¹ and/orR² may be one, wherein 1 or 2 hydrogen atoms thereof are replaced by analkyl group having generally 1 to 6, preferably 1 to 4 carbon atoms,which is straight chained, branched or cyclic.

The aminoalkyl group as a substituent of the group represented by R¹and/or R² includes one, wherein at least one hydrogen atom of the alkylgroup represented by R¹ and/or R² is replaced by the above amino group.

The alkylcarbamoyl group as a substituent of the group represented by R¹and/or R² includes one, wherein 1 or 2 hydrogen atoms of the carbamoylgroup are each independently replaced by the above alkyl group, which isspecifically exemplified by, for example, a methylcarbamoyl group, anethylcarbamoyl group, a n-propylcarbamoyl group, an isopropylcarbamoylgroup, a n-butylcarbamoyl group, an isobutylcarbamoyl group, atert-butylcarbamoyl group, a pentylcarbamoyl group, a hexylcarbamoylgroup, a heptylcarbamoyl group, an octylcarbamoyl group, anonylcarbamoyl group, a decylcarbamoyl group, a dodecylcarbamoyl group,a tetradecylcarbamoyl group, a pentadecylcarbamoyl group, ahexadecylcarbamoyl group, a heptadecylcarbamoyl group, anonadecylcarbamoyl group, an icosylcarbamoyl group, acyclopentylcarbamoyl group, a cyclohexylcarbamoyl group, acycloheptylcarbamoyl group, dimethylcarbamoyl group, anethylmethylcarbamoyl group, diethylcarbamoyl group, amethylpropylcarbamoyl group, dipropylcarbamoyl group, anethylhexylcarbamoyl group, a dibutylcarbamoyl group, aheptylmethylcarbamoyl group, a methyloctylcarbamoyl group, adecylmethylcarbamoyl group, a dodecylethylcarbamoyl group, amethylpentadecylcarbamoyl group, an ethyloctadecylcarbamoyl group, acyclopentylmethylcarbamoyl group, a cyclohexylmethylcarbamoyl group, acyclohexylethylcarbamoyl group, a cyclohexylpropylcarbamoyl group, acyclohexylbutylcarbamoyl group and a dicyclohexylcarbamoyl group.

Among the compounds represented by the general formula [1], deuterationof the compound having a substituent such as an alkoxycarbonyl group, anaryloxycarbonyl group and a cyano group, which is labile todecomposition under acidic or basic condition, can efficiently provide adesired deuterated compound without decomposition of these substituentsby the use of the method of the present invention.

In a method for deuteration of the present invention, the heavy hydrogensource to be reacted with the above compound represented by the generalformula [1] includes, for example, heavy hydrogen gas (D₂, T₂) and adeuterated solvent. As a heavy hydrogen source for deuteration of thecompound represented by the general formula [1], a deuterated solvent isparticularly preferable when X is a carbonyl group, and also adeuterated solvent is preferable when X is a hydroxylmethylene group.

Specific examples of the deuterated solvent as a heavy hydrogen sourceinclude, in the case where heavy hydrogen is deuterium, for example,deuterium oxide (D₂O); deuterated alcohols such as deuterated methanol,deuterated ethanol, deuterated isopropanol, deuterated butanol,deuterated tert-butanol, deuterated pentanol, deuterated hexanol,deuterated heptanol, deuterated octanol, deuterated nonanol, deuterateddecanol, deuterated undecanol and deuterated dodecanol; deuteratedcarboxylic acids such as deuterated formic acid, deuterated acetic acid,deuterated propionic acid, deuterated butyric acid, deuteratedisobutyric acid, deuterated-valeric acid, deuterated isovaleric acid anddeuterated pivalic acid; deuterated ketones such as deuterated acetone,deuterated methylethylketone, deuterated methylisobutyl ketone,deuterated diethylketone, deuterated dipropylketone, deuterateddiisopropylketone and deuterated dibutylketone; and organic solventssuch as deuterated dimethylsulfoxide, and among others, deuterium oxideand deuterated alcohols are preferable, and deuterium oxide anddeuterated methanol are more preferable. In view of environmental aspectand workability, deuterium oxide is preferable. In the case where aheavy hydrogen is tritium, specific examples of the deuterated solventas a heavy hydrogen source include, for example, tritium oxide (T₂O),etc.

The deuterated solvent may be one, wherein at least one hydrogen atom inthe molecule is deuterated, and for example, deuterated alcohols whereinat least a hydrogen atom in a hydroxyl group is deuterated, ordeuterated carboxylic acids wherein at least a hydrogen atom in acarboxyl group is deuterated, can be used in a method for deuteration ofthe present invention, and among others, a solvent wherein all hydrogenatoms in the molecule are deuterated is particularly preferable.

As an amount of heavy hydrogen source to be used is increasing,deuteration of the present invention tends to proceed further, however,in view of cost, the amount of a heavy hydrogen atom contained in heavyhydrogen source to be used is such level, as lower limit, preferably inthe order of, equimolar, 10 molar times, 20 molar times, 30 molar timesand 40 molar times, and as upper limit, preferably in the order or, 250molar times and 150 molar times, relative to hydrogen atoms deuteratablein the compound represented by the general formula [1] as a reactivesubstrate.

In a method for deuteration of the present invention, a reaction solventmay be used, if necessary. In the case where a reactive substrate isliquid, use of a reaction solvent is not necessary, even if heavyhydrogen gas is used as a heavy hydrogen source, and in the case where areactive substrate is solid, use of a reaction solvent is not required,when a deuterated solvent is used as a heavy hydrogen source, however,use of a suitable reaction solvent is necessary when a reactivesubstrate is solid and heavy hydrogen source is heavy hydrogen gas.

In the case where a compound having a carbon-carbon double bond or acarbon-carbon triple bond is deuterated, a deuterated solvent ispreferably used as a heavy hydrogen source because these groups arereduced by so-called hydrogenation in contact with hydrogen gas or heavyhydrogen gas in the presence of a catalyst.

The reaction solvent to be used if necessary is preferably one notdeuterated by heavy hydrogen gas used as heavy hydrogen source, or suchone as even when deuterated by heavy hydrogen gas, said deuteratedreaction solvent can be used as it is as heavy hydrogen source fordeuteration of the present invention. A reaction solvent, which hardlydissolves a substrate, can be used, because a reaction system ofdeuteration of the present invention may be in suspension state,however, one, which easily dissolves a substrate, is preferable.

Specific examples of the reaction solvent to be used, if necessary,include organic solvents, which is not deuteratable by heavy hydrogengas, such as ethers including dimethyl ether, diethyl ether, diisopropylether, ethylmethyl ether, tert-butylmethyl ether, 1,2-dimethoxyethane,oxirane, 1,4-dioxane, dihydropyran and tetrahydrofuran; aliphatichydrocarbons including hexane, heptane, octane, nonane, decane andcyclohexane; organic solvents, which can be usable as heavy hydrogensource of the present invention even if deuterated by heavy hydrogengas, such as alcohols including methanol, ethanol, isopropanol, butanol,tert-butanol, pentanol, hexanol, heptanol, octanol, nonanol, decanol,undecanol and dodecanol, carboxylic acids including formic acid, aceticacid, propionic acid, butyric acid, isobutyric acid, valeric acid,isovaleric acid and pivalic acid, ketones such as acetone, methyl ethylketone, methyl isobutyl ketone, diethyl ketone, dipropyl ketone,diisopropyl ketone and dibutyl ketone, and dimethylsulfoxide.

The activated catalyst selected from a palladium catalyst, a platinumcatalyst, a rhodium catalyst, a ruthenium catalyst, a nickel catalystand a cobalt catalyst in the present invention (hereinafter may beabbreviated as an “activated catalyst”) means a so-called palladiumcatalyst, a platinum catalyst, a rhodium catalyst, a ruthenium catalyst,a nickel catalyst or a cobalt catalyst (hereinafter may be abbreviatedas a “non-activated catalyst” or simply as a “catalyst”) which isactivated by contacting with hydrogen gas or heavy hydrogen gas.

In a method for deuteration of the present invention, deuteration may becarried out using a catalyst activated in advance, or activation of acatalyst and deuteration of a reactive substrate may be carried outsimultaneously in the co-presence of a non-activated catalyst andhydrogen gas or heavy hydrogen gas in the deuteration reaction system.However, when a compound having a carbon-carbon double bond or triplebond is deuterated among the compounds represented by the generalformula [1], since presence of hydrogen gas or heavy hydrogen gas in areaction system causes hydrogenation, a catalyst activated in advance ispreferably used to avoid such hydrogenation.

When deuteration is carried out using the catalyst activated by hydrogengas or heavy hydrogen gas in advance, a part of gas phase in adeuteration reactor may be replaced with an inert gas such as nitrogenand argon.

When a deuteration reaction of the present invention is carried out inthe presence of hydrogen gas or heavy hydrogen gas in a reaction system,the reaction may be carried out by directly passing hydrogen gas orheavy hydrogen gas through a reaction solution, or replacing a part ofgas phase in a reactor with hydrogen gas or heavy hydrogen gas.

In the case where a compound not having a carbon-carbon double bond ortriple bond is deuterated among the compounds represented by the generalformula [1], deuteration reaction can be carried out by replacing a partof gas phase in a deuteration reactor with hydrogen or heavy hydrogeneven if a catalyst activated in advance is used.

In a method for deuteration of the present invention, a reactor ispreferably in a sealed state or nearly sealed state (hereinafter may beabbreviated as “sealed state”) so that the reaction system is, as theresult, in pressurized state. Nearly sealed state involves, for example,a case of so-called continuous reaction where a reactive substrate iscontinuously charged into a reactor and a product is continuously takenout therefrom.

In a method for deuteration of the present invention, wherein a reactoris in sealed state, temperature of a reaction system can be easilyelevated to perform deuteration efficiently.

Further, by carrying out deuteration of a reactive substrate andactivation of a catalyst simultaneously using a method replacing a partof gas phase in a deuteration reactor with hydrogen gas or heavyhydrogen gas, deuteration of the compound represented by the generalformula [1], except one having a carbon-carbon double bond and/or triplebond, can be performed further more efficiently because such acomplicated process that a catalyst is activated in advance is notrequired.

Furthermore, in the case where a catalyst activated by hydrogen gas orheavy hydrogen gas in advance is used in deuteration in sealed state,only deuteration proceeds without reduction, even when a substrate is acompound generally labile to reduction by hydrogen gas, and the likesuch as one having a carbon-carbon double bond and/or triple bond,because hydrogen gas or heavy hydrogen gas is not present in thedeuteration reactor.

The activated catalyst in the present invention includes, a palladiumcatalyst, a platinum catalyst, a rhodium catalyst, a ruthenium catalyst,a nickel catalyst and a cobalt catalyst, as described above, and amongothers, a palladium catalyst, a platinum catalyst and a rhodium catalystis preferable, a palladium catalyst and a platinum catalyst is morepreferable, and a palladium catalyst is particularly preferable. Thesecatalysts can be used effectively in a method for deuteration of thepresent invention by themselves or in combination accordingly.

The palladium catalyst includes one having generally 0 to 4, preferably0 to 2 and more preferably 0 valence of a palladium atom.

The platinum catalyst includes one having generally 0 to 4, preferably 0to 2 and more preferably 0 valence of a platinum atom.

The rhodium catalyst includes one having generally 0 or 1, preferably 0valence of a rhodium atom.

The ruthenium catalyst includes one having generally 0 to 2, preferably0 valence of a ruthenium atom.

The nickel catalyst includes one having generally 0 to 2, preferably 0valence of a nickel atom.

The cobalt catalyst includes one having generally 0 or 1, preferably 0valence of a cobalt atom.

The above catalyst may be a metal itself or oxides, halides or acetatesof the above metals, and the metal catalyst may be coordinated with aligand or may be one consisting of these metals, metal oxides, metalhalides, metal acetates or metal complexes, supported on variouscarriers.

Hereinafter, a catalyst supported on a carrier may be abbreviated as a“carrier-supported metal catalyst”, and a catalyst not supported on acarrier may be abbreviated as a “metal catalyst”.

Among catalysts, in a method for deuteration of the present invention, aligand of the metal catalyst which may be coordinated with a ligand,includes, for example, 1,5-cyclooctadiene (COD), dibenzylideneacetone(DBA), bipyridine (BPY), phenanthroline (PHE), benzonitrile (PhCN),isocyanide (RNC), triethylarsine (As(Et)₃), acetylacetone (acac);organic phosphine ligands such as dimethylphenylphosphine (P(CH₃)₂Ph),diphenylphosphinoferrocene (DPPF), trimethylphosphine (P(CH₃)₃),triethylphosphine (PEt₃), tri-tert-butylphosphine(P^(t)Bu₃),tricyclohexylphosphine (PCy₃), trimethoxyphosphine (P(OCH₃)₃),triethoxyphosphine (P(OEt)₃), tri-tert-butoxyphosphine (P(O^(t)Bu)₃),triphenylphosphine (PPh₃), 1,2-bis(diphenylphosphino)ethane (DPPE),triphenoxyphosphine (P(OPh)₃) and tri-o-tolylphosphine (P(o-tolyl)₃).

Specific examples of the palladium based metal catalyst include, forexample, Pd; palladium hydroxide catalysts such as Pd(OH)₂; palladiumoxide catalysts such as PdO; halogenated palladium catalysts such asPdBr₂, PdCl₂ and PdI₂; palladium acetate catalysts such as palladiumacetate (Pd(OAc)₂) and palladium trifluoroacetate (Pd(OCOCF₃)₂); andpalladium metal complex catalysts coordinated with a ligand such asPd(RNC)₂Cl₂, Pd(acac)₂, diacetate-bis(triphenylphosphine)palladium[Pd(OAc)₂(PPh₃)₂], Pd(PPh₃)₄, Pd₂(dba)₃, Pd(NH₃)₂Cl₂, Pd(CH₃CN)₂Cl₂,dichlorobis(benzonitrile)palladium [Pd(PhCN)₂Cl₂], Pd(dppe)Cl₂,Pd(dppf)Cl₂, Pd(PCy₃)₂Cl₂, Pd(PPh₃)₂Cl₂, Pd[P(o-tolyl)₃]₂Cl₂,Pd(cod)₂Cl₂ and Pd(PPh₃)(CH₃CN)₂Cl₂.

Specific examples of the platinum based metal catalyst include, forexample, Pt; platinum catalysts such as PtO₂, PtCl₄, PtCl₂ and K₂PtCl₄;and platinum metal complex catalysts coordinated with a ligand such asPtCl₂(cod), PtCl₂(dba), PtCl₂(PCy₃)₂, PtCl₂(P(OEt)₃)₂, PtCl₂(P(OtBu)₃)₂,PtCl₂(bpy), PtCl₂(phe), Pt(PPh₃)₄, Pt(cod)₂, Pt(dba)₂, Pt(bpy)₂ andPt(phe)₂.

Specific examples of the rhodium based metal catalyst include, forexample, Rh and rhodium metal complex catalysts coordinated with aligand such as RhCl(PPh₃)₃.

Specific examples of the ruthenium based metal catalyst include, forexample, Ru and ruthenium metal complex catalysts coordinated with aligand such as RuCl₂(PPh₃)₃.

Specific examples of the nickel based metal catalyst include, forexample, Ni, nickel catalysts such as NiCl₂ and NiO, and nickel metalcomplex catalysts coordinated with a ligand such as NiCl₂(dppe),NiCl₂(PPh₃)₂, Ni(PPh₃)₄, Ni(P(OPh)₃)₄ and Ni(cod)₂.

Specific examples of the cobalt based metal catalyst include, forexample, cobalt metal complex catalysts coordinated with a ligand suchas CO(C₃H₅){P(OCH₃)₃}₃.

The carrier, in the case where the above catalyst is supported on acarrier, includes, for example, carbon, alumina, silica gel, zeolite,molecular sieve, ion-exchange resins and polymers, and among others,carbon is preferable.

The ion exchange resin to be used as a carrier may be one having noadverse effect on deuteration of the present invention, and includes,for example, a cation exchange resin and an anion exchange resin.

The cation exchange resin includes, for example, a weak acidic cationexchange resin and a strong acidic cation exchange resin. The anionexchange resin includes, for example, a weak basic anion exchange resinand a strong basic anion exchange resin.

The ion exchange resin generally contains a polymer cross-linked with adifunctional monomer, as a skeleton polymer, to which an acidic group ora basic group is bonded and then is exchanged by various cations andanions (a counter ion), respectively.

Specific examples of the weak acidic cation exchange resin include, forexample, one obtained by hydrolysis of a polymer of acrylate ester or amethacrylate ester, cross-linked by divinylbenzene.

Specific examples of the strong acidic cation exchange resin include,for example, one obtained by sulfonation of a copolymer ofstyrene-divinylbenzene.

Specific examples of the strong basic anion exchange resin include onewherein an amino group is bonded to an aromatic ring of a copolymer ofstylene-divinylbenzene.

Strength of basicity of a basic anion exchange resin increases with anamino group bonded in the order of a primary amino group, a secondaryamino group, a tertiary amino group and a quaternary ammonium salt.

The ion exchange resin generally available on the market may be used aswell as the above ion exchange resin.

The polymer to be used as a carrier is not especially limited as long asit has no adverse effect on deuteration of the present invention,however, specific examples of such a polymer include, for example, oneobtained by polymerization or copolymerization of a monomer representedby the following general formula [2]:

wherein R³ represents a hydrogen atom, a lower alkyl group, a carboxylgroup, a carboxyalkyl group, an alkoxycarbonyl group, ahydroxyalkoxycarbonyl group, a cyano group or a formyl group; R⁴represents a hydrogen atom, a lower alkyl group, a carboxyl group, analkoxycarbonyl group, a hydroxyalkoxycarbonyl group, a cyano group or ahalogen atom; R⁵ represents a hydrogen atom, a lower alkyl group, ahaloalkyl group, a hydroxyl group, an aryl group which may have asubstituent, an aliphatic heterocyclic group, an aromatic heterocyclicgroup, a halogen atom, an alkoxycarbonyl group, a hydroxyalkoxycarbonylgroup, a sulfo group, a cyano group, a cyano-containing alkyl group, anacyloxy group, a carboxyl group, a carboxyalkyl group, an aldehydegroup, an amino group, an aminoalkyl group, a carbamoyl group, aN-alkylcarbamoyl group or a hydroxyalkyl group, and R⁴ and R⁵ may forman alicyclic ring together with the adjacent —C═C— bond.

In the general formula [2], the lower alkyl group represented by R³ toR⁵ may be straight chained, branched or cyclic, and includes, forexample, an alkyl group having 1 to 6 carbon atoms, which isspecifically exemplified by a methyl group, an ethyl group, a n-propylgroup, an isopropyl group, a n-butyl group, an isobutyl group, atert-butyl group, a sec-butyl group, a n-pentyl group, an isopentylgroup, a tert-pentyl group, a 1-methylpentyl group, a n-hexyl group, anisohexyl group, a cyclopropyl group, a cyclopentyl group and acyclohexyl group.

The carboxyalkyl group represented by R³ and R⁴ includes, for example,one wherein a part of hydrogen atoms of the above lower alkyl group isreplaced by a carboxyl group, which is specifically exemplified by, forexample, a carboxymethyl group, a carboxyethyl group, a carboxypropylgroup, a carboxybutyl group, a carboxypentyl group and a carboxyhexylgroup.

The alkoxycarbonyl group represented by R³ to R⁵ includes, for example,preferably one having 2 to 11 carbon atoms, which is specificallyexemplified by, for example, a methoxycarbonyl group, an ethoxycarbonylgroup, a propoxycarbonyl group, a butoxycarbonyl group, apentyloxycarbonyl group, a hexyloxycarbonyl group, a heptyloxycarbonylgroup, a 2-ethylhexyloxycarbonyl group, an octyloxycarbonyl group, anonyloxycarbonyl group and a decyloxycarbonyl group.

The hydroxyalkoxycarbonyl group represented by R³ to R⁵ includes onewherein a part of hydrogen atoms of the above alkoxycarbonyl grouphaving 2 to 11 carbon atoms is replaced by a hydroxyl group, which isspecifically exemplified by, for example, a hydroxymethyloxycarbonylgroup, a hydroxyethyloxycarbonyl group, a hydroxypropyloxycarbonylgroup, a hydroxybutyloxycarbonyl group, a hydroxypentyloxycarbonylgroup, a hydroxyhexyloxycarbonyl group, a hydroxyheptyloxycarbonylgroup, a hydroxyoctyloxycarbonyl group, a hydroxynonyloxycarbonyl groupand a hydroxydecyloxycarbonyl group.

The halogen atom represented by R⁴ and R⁵ includes, for example,fluorine, chlorine, bromine and iodine.

The haloalkyl group represented by R⁵ includes, for example, one having1 to 6 carbon atoms, wherein the above lower alkyl group represented byR³ to R⁵ is halogenated (for example, fluorinated, chlorinated,brominated, iodinated, etc.), which is specifically exemplified by, forexample, a chloromethyl group, a bromomethyl group, a trifluoromethylgroup, a 2-chloroethyl group, a 3-chloropropyl group, a 3-bromopropylgroup, a 3,3,3-trifluoropropyl group, a 4-chlorobutyl group, a5-chloropentyl group and a 6-chlorohexyl group.

The aryl group of the aryl group which may have a substituent includes,for example, a phenyl group, a tolyl group, a xylyl group and a naphthylgroup, and said substituent includes, for example, an amino group, ahydroxyl group, a lower alkoxy group and a carboxyl group. Specificexamples of the substituted aryl group include, for example, anaminophenyl group, a toluidino group, a hydroxyphenyl group, amethoxyphenyl group, a tert-butoxyphenyl group and a carboxyphenylgroup.

The aliphatic heterocyclic group includes, for example, preferably a 5-or 6-membered one having 1 to 3 hetero atoms such as a nitrogen atom, anoxygen atom and a sulfur atom, which is specifically exemplified by, forexample, a 2-oxopyrrolidyl group, a piperidyl group, a piperidino group,a piperazinyl group and a morpholino group.

The aromatic heterocyclic group includes, for example, preferably a 5-or 6-membered one having 1 to 3 hetero atoms such as a nitrogen atom, anoxygen atom and a sulfur atom, which is specifically exemplified by, forexample, a pyridyl group, an imidazolyl group, a thiazolyl group, afuryl group and a pyranyl group.

The cyano-containing alkyl group includes, for example, one wherein apart of hydrogen atoms of the above lower alkyl group is replaced by acyano group, which is specifically exemplified by, for example, acyanomethyl group, a 2-cyanoethyl group, a 2-cyanopropyl group, a3-cyanopropyl group, a 2-cyanobutyl group, a 4-cyanobutyl group, a5-cyanopentyl group and a 6-cyanohexyl group.

The acyloxy group includes, for example, one derived from a carboxylicacid having 2 to 20 carbon atoms, which is specifically exemplified by,for example, an acetyloxy group, a propionyloxy group, a butyryloxygroup, a pentanoyloxy group, a nonanoyloxy group, a decanoyloxy groupand a benzoyloxy group.

The aminoalkyl group includes one wherein a part of hydrogen atoms ofthe above lower alkyl group is replaced by an amino group, which isspecifically exemplified by, for example, an aminomethyl group, anaminoethyl group, an aminopropyl group, an aminombutyl group, anaminopentyl group and an aminohexyl group.

The N-alkylcarbamoyl group includes one wherein a part of hydrogen atomsof a carbamoyl group is replaced by an alkyl group, which isspecifically exemplified by, for example, an N-methylcarbamoyl group, anN-ethylcarbamoyl group, an N-n-propylcarbamoyl group, anN-isopropylcarbamoyl group, an N-n-butylcarbamoyl group and anN-tert-butylcarbamoyl group.

The hydroxyalkyl group includes one wherein a part of hydrogen atoms ofthe above lower alkyl group is replaced by a hydroxyl group, which isspecifically exemplified by, for example, a hydroxymethyl group, ahydroxyethyl group, a hydroxypropyl group, a hydroxybutyl group, ahydroxypentyl group and a hydroxyhexyl group.

The aliphatic ring in the case where R⁴ and R⁵ are bonded together withthe adjacent —C═C— bond to form an alicyclic ring, includes, forexample, an unsaturated alicyclic ring having 5 to 10 carbon atoms, andmay be monocyclic or polycyclic, which is specifically exemplified by,for example, a norbornene ring, a cyclopentene ring, a cyclohexene ring,a cyclooctene ring and a cyclodecene ring.

The specific examples of the monomer represented by the general formula[2] include, for example, ethylenically unsaturated aliphatichydrocarbons having 2 to 20 carbon atoms such as ethylene, propylene,butylene and isobutylene; ethylenically unsaturated aromatichydrocarbons having 8 to 20 carbon atoms such as styrene,4-methylstyrene, 4-ethylstyrene and divinylbenzene; alkenyl estershaving 3 to 20 carbon atoms such as vinyl formate, vinyl acetate, vinylpropionate and isopropenyl acetate; halogen-containing ethylenicallyunsaturated compounds having 2 to 20 carbon atoms such as vinylchloride, vinylidene chloride, vinylidene fluoride andtetrafluoroethylene; ethylenically unsaturated carboxylic acids having 3to 20 carbon atoms such as acrylic acid, methacrylic acid, itaconicacid, maleic acid, fumaric acid, crotonic acid, vinylacetic acid,allylacetic acid and vinylbenzoic acid (these acids may form a salt ofalkali metals such as sodium and potassium, or an ammonium salt);ethylenically unsaturated carboxylic acid esters such as methylmethacrylate, ethyl methacrylate, propyl methacrylate, butylmethacrylate, 2-ethylhexyl methacrylate, methyl acrylate, ethylacrylate, propyl acrylate, butyl acrylate, 2-ethylhexyl acrylate, laurylmethacrylate, stearyl acrylate, methyl itaconate, ethyl itaconate,methyl maleate, ethyl maleate, methyl fumarate, ethyl fumarate, methylcrotonate, ethyl crotonate and methyl 3-butenoate; cyano-containingethylenically unsaturated compounds having 3 to 20 carbon atoms such asacrylonitrile, methacrylonitrile and allyl cyanide; ethylenicallyunsaturated amide compounds having 3 to 20 carbon atoms such asacrylamide and methacrylamide; ethylenically unsaturated aldehydeshaving 3 to 20 carbon atoms such as acrolein and crotonaldehyde;ethylenically unsaturated sulfonic acids having 2 to 20 carbon atomssuch as vinylsulfonic acid and 4-vinylbenzene sulfonic acid (these acidsmay form a salt of alkali metals such as sodium and potassium);ethylenically unsaturated aliphatic amines having 2 to 20 carbon atomssuch as vinylamine and allylamine; ethylenically unsaturated aromaticamines having 8 to 20 carbon atoms such as vinylaniline; ethylenicallyunsaturated aliphatic heterocyclic amines having 5 to 20 carbon atomssuch as N-vinylpyrrolidone and vinylpiperidine; ethylenicallyunsaturated alcohols having 3 to 20 carbon atoms such as allyl alcoholand crotyl alcohol; and ethylenically unsaturated phenols having 8 to 20carbon atoms such as 4-vinylphenol.

When the above polymer is used as a carrier, use of the carrier that ishardly deuterated itself by deuteration of the present invention ispreferable, however, a catalyst supported on the carrier deuteratableitself can be also used for deuteration of the present invention.

In a method for deuteration of the present invention, among thecatalysts supported on a carrier, a carrier-supported palladiumcatalyst, a carrier-supported platinum catalyst and a carrier-supportedrhodium catalyst are preferably used. Among others, a carrier-supportedpalladium catalyst is preferable and specifically a palladium carbon isparticularly preferable.

In the carrier-supported catalysts, a ratio of palladium, platinum,rhodium, ruthenium, nickel or cobalt, as a catalyst metal is generally 1to 99% by weight, preferably 1 to 50% by weight, more preferably 1 to30% by weight, further more preferably 1 to 20% by weight andparticularly preferably 5 to 10% by weight, based on the whole catalyst.

In a method for deuteration of the present invention, an amount of theactivated catalyst or non-activated catalyst to be used is generallyso-called catalyst quantity, and preferably in the order 0.01 to 200% byweight, 0.01 to 100% by weight, 0.01 to 50% by weight, 0.01 to 20% byweight, 0.1 to 20% by weight, 1 to 20% by weight and 10 to 20% byweight, relative to the compound represented by the general formula [1]to be used as a reactive substrate, irrespective of whether the catalystis supported on a carrier or not, and the upper limit content of thecatalyst metal in said whole catalyst is preferably in the order of, 20%by weight, 10% by weight, 5% by weight and 2% by weight, while the lowerlimit thereof is preferably in the order of, 0.0005% by weight, 0.005%by weight, 0.05% by weight and 0.5% by weight.

When a compound represented by the above general formula [1] isdeuterated, two or more kinds of the various catalysts as describedabove can be used in an appropriate combination as a catalyst. Suchcombined use of the catalysts can sometimes improve deuteration ratio.For example, in the case where a compound represented by the generalformula [1], wherein X is a hydroxymethylene group, is deuterated,specific examples of the combination of catalysts to improve deuterationratio include, for example, a combination of a palladium catalyst and aplatinum catalyst, a ruthenium catalyst or a rhodium catalyst, acombination of a platinum catalyst and a ruthenium catalyst or a rhodiumcatalyst, and a combination of a ruthenium catalyst and a rhodiumcatalyst, and among others, preferably a combination of a palladiumcatalyst and a platinum catalyst, wherein any one or both thereof may besupported on a carrier. Specific examples of the combination of apalladium catalyst and a platinum catalyst include, for example, acombination of a palladium carbon and a platinum carbon.

In the case where two or more kinds of catalysts are used incombination, amounts of the catalysts to be used may be determined sothat the total amount of the catalysts becomes the amount of thecatalyst to be used as described above an amount ratio of each catalystto be used is not especially limited, however, when a palladium carbonand a platinum carbon are used in combination as described above, anamount of each catalyst to be used may be determined so that weight ofpalladium in the whole catalyst becomes generally 0.01 to 100 times,preferably 0.1 to 10 times and more preferably 0.2 to 5 times, relativeto weight of platinum.

In the case where a non-activated catalyst is used in the reaction ofthe present invention, an amount of hydrogen to be used, whereinhydrogen is present in the reaction system to activate the catalyst, maybe a necessary amount to activate the catalyst, and the amount isgenerally 1 to 20,000 equivalents and preferably 10 to 700 equivalents,relative to the catalyst, because these is possibility that an excessiveamount of hydrogen shows adverse effect on a deuteration reaction of thepresent invention, such as hydrogenation of a deuterated solvent as aheavy hydrogen source and decrease of a ratio of heavy hydrogen as aheavy hydrogen source in the reaction system.

Further, in the case where heavy hydrogen is present in the reactionsystem to activate the catalyst, an amount of heavy hydrogen to be usedmay be a necessary amount to activate the catalyst, and the amount isgenerally 1 to 20,000 equivalents and preferably 10 to 700 equivalents,relative to the catalyst, however, even if the amount of said heavyhydrogen is excessively large, deuteration of the present invention canbe performed without any problem, because said heavy hydrogen can bealso used as a heavy hydrogen source of the present invention.

In a method for deuteration of the present invention, the lower limit ofreaction temperature is generally 10° C., and preferably in order of,20° C., 40° C., 60° C., 80° C., 110° C., 140° C. and 160° C., and theupper limit thereof is generally 300° C., and preferably in order of200° C. and 180° C.

In a method for deuteration of the present invention, a reaction time isgenerally 30 minutes to 72 hours, preferably 1 to 48 hours, morepreferably 3 to 30 hours, and further more preferably-6 to 24 hours.

The method for deuteration of the present invention will be specificallyexplained by taking, as an example, the case of using heavy water as aheavy hydrogen source and a palladium carbon catalyst (Pd/C) (Pdcontent: 10%) as a non-activated catalyst.

Namely, for example, 1 mole of a compound represented by the generalformula [1] not having a carbon-carbon double bond nor a carbon-carbontriple bond in structure thereof (substrate) and 0.01 to 200% by weightof a non-activated Pd/C relative to said substrate are added to suchamount of heavy water that 10 to 150 molar times of heavy hydrogen atomsrelative to deuteratable hydrogen atoms in the substrate are containedtherein, followed by replacing atmosphere of a sealed reaction system byhydrogen and reacting, with stirring in an oil bath at about 110° C. to200° C. for about 1 to 48 hours. After completion of the reaction, whenthe reaction product is soluble in a deuterated solvent, the catalyst isfiltered off from the reaction solution, and the filtrate isconcentrated to isolate the product which is subjected to structuralanalysis by ¹H-NMR, ²H-NMR and mass spectrum measurements.

When the reaction product is hardly soluble in the deuterated solvent,the reaction product is isolated from the reaction solution and thensubjected to structural analysis by ¹H-NMR, ²H-NMR and mass spectrummeasurements. In the case where isolation of the reaction product fromthe reaction solution is difficult, the filtrate as it is may besubjected to measurement of ¹H-NMR to perform structural analysis byusing an appropriate internal standard substance.

When the product is hardly soluble in a deuterated solvent, theisolation of the product from the reaction solution may be carried outaccording to known purification methods such as extraction of theproduct from the reaction solution using an organic solvent, in whichthe product is soluble and then filtering off the catalyst.

The method for deuteration of the present invention will further beexplained specifically by taking, as another example, the case of usingheavy water as a heavy hydrogen source and a palladium carbon catalyst(Pd content: 10%) activated by hydrogen gas as a catalyst activated inadvance.

Namely, for example, 1 mole of a compound represented by the generalformula [1] having a carbon-carbon double bond or a carbon-carbon triplebond in structure thereof (substrate) and 0.01 to 200% by weight of aPd/C catalyst, relative to said substrate, activated by contacting withhydrogen gas in advance are added to such amount of heavy water that 10to 150 molar times of heavy hydrogen atoms relative to deuteratablehydrogen atoms in the substrate are contained therein, followed byreplacing atmosphere of a sealed reaction system with inert gas andreacting with stirring in an oil bath at about 110° C. to 200° C. forabout 1 to 48 hours. After completion of the reaction, when the reactionproduct is soluble in a deuterated solvent, the catalyst is filtered outfrom the reaction solution, and the filtrate is concentrated to isolatethe product which is subjected to structural analysis by ¹H-NMR, ²H-NMRand mass spectrum measurements.

When the reaction product is hardly soluble in the deuterated solvent,the reaction product is isolated from the reaction solution and thensubjected to structural analysis by ¹H-NMR, ²H-NMR and mass spectrummeasurements. In the case where isolation of the reaction product fromthe reaction solution is difficult, the filtrate as it is may besubjected to measurement of ¹H-NMR to perform structural analysis byusing an appropriate internal standard substance. Isolation of theproduct from the reaction solution may be carried out in the same manneras of the isolation method In a method for deuteration of the presentinvention using a non-activated catalyst. Further, when the product ishardly soluble in a deuterated solvent, isolation of the product fromthe reaction solution may be carried out according to known purificationmethods such as extraction of the product from the reaction solutionusing an organic solvent and the like, in which the product is solubleand then filtering off the catalyst.

Further, among the methods for deuteration of the present invention, forexample, by the method using a palladium carbon catalyst and a platinumcarbon catalyst in combination, tricyclo[5.2.1.0^(2,6)]decan-8-ol,wherein deuteration ratio thereof is generally not less than 60%,preferably in order of, not less than 70%, not less than 78%, not lessthan 80%, not less than 85%, not less than 88%, not less than 89% andnot less than 90%, can be easily obtained. Thus obtained deuteratedtricyclo[5.2.1.0^(2,6)]decan-8-ol is a very useful compound, forexample, as a raw material of deuterated methacrylate ester for apolymer of optical fiber.

As described above, the method for deuteration of the present inventionusing a catalyst activated in advance as an activated catalyst and adeute rated solvent as a heavy hydrogen source, can perform only thedesired deuteration, even when a compound represented by the generalformula [1] has a carbon-carbon double bond or a carbon-carbon triplebond, without reduction of the double or triple bond by hydrogenation,and even when said compound has a substituent such as a nitro group anda cyano group, without reduction of these substituents.

When a compound represented by the general formula [1] has acarbon-carbon double bond or triple bond, wherein these bonds tend to beeasily polymerized during the deuteration reaction of the presentinvention, for example, a polymerization inhibitor, and the like may beadded to the reaction system of the deuteration reaction to inhibit thepolymerization reaction.

As described above, the method for deuteration of the present invention,comprising reacting a compound represented by the general formula [1]with a heavy hydrogen source in the co-presence of an activatedcatalyst, enables to efficiently carry out the deuteration (replacementby deuterium or tritium) of a compound having a carbonyl group and asecondary alcohol compound, irrespective of presence or absence of adouble bond or triple bond in the compound or presence or absence of asubstituent and a type thereof.

Further, the method for deuteration of the present invention can notonly improve a working environment but also be applied to deuteration ofa substrate which is labile to decomposition at high temperature orunder acidic or basic condition, because the deuteration reaction can becarried out without making the reaction condition particularly acidic orbasic.

Furthermore, in a compound represented by the general formula [1]wherein X is a carbonyl group, the method for deuteration of the presentinvention enables to efficiently deuterate not only a hydrogen atomlocating near the carbonyl group but also a hydrogen atom locating farfrom the carbonyl group.

Further, in a compound represented by the general formula [1] wherein Xis a hydroxymethylene group, the method for deuteration of the presentinvention enables to efficiently deuterate not only a hydrogen atomlocating far from the hydroxyl group but also a hydrogen atom locatingnear the hydroxyl group.

Still further, among the compounds represented by the general formula[1], particularly in tricyclo[5.2.1.0^(2,6)]decan-8-ol, the method fordeuteration of the present invention enables to obtain one wherein adeuteration ratio thereof is higher than the level that can be achievedby conventional methods.

In the following, the present invention will be explained in furtherdetail referring to Examples, but the present invention is not limitedthereto by any means.

In the Examples, following catalysts were used: palladium carbon (Pd/C)with Pd content of 10%, platinum carbon (Pt/C) with Pt content of 5%,ruthenium carbon (Ru/C) with Ru content of 5% and rhodium carbon (Rh/C)with Rh content of 5%.

EXAMPLE Example 1

In 17 mL of deuterium oxide (D₂O) were suspended 500 mg of 4-heptanone(substance) and 50 mg of palladium carbon, followed by replacingatmosphere of a sealed reaction system with hydrogen gas and conductinga reaction in an oil bath at 160° C. for about 24 hours. Aftercompletion of the reaction, the reaction solution was extracted withether, followed by filtering off the catalyst from the obtained extractand concentration of the filtrate under reduced pressure to obtain aproduct, which was subjected to structural analysis by ¹H-NMR, ²H-NMRand mass spectrum measurements. Isolation yield of the objective productwas 46% and deuteration ratio of the substrate was 97%.

Example 2

In 17 mL of deuterium oxide were suspended 500 mg of acetone (substrate)and 50 mg of palladium carbon, followed by replacing the atmosphere of areaction system with hydrogen gas and conducting a reaction in an oilbath at 110° C. for about 24 hours. After completion of the reaction,the catalyst was filtered off from the reaction solution. In thefiltrate was added dioxane as an internal standard and then subjected tostructural analysis by ¹H-NMR measurement. Deuteration ratio of thesubstrate was 99%.

Examples 3 to 15

The same deuteration reactions as in Example 1 were conducted, exceptfor using substrates as deuteration targets and catalysts shown in thefollowing Table 1 and conducting at each temperature shown in Table 1.Isolation yields and deuteration ratios of the obtained compounds areshown in Table 1. In Table 1, deuteration ratios of 2-butanone,2-norbornanone, tricyclo[5.2.1.0^(2,6)]decane-8-one, norborneol,tricyclo[5.2.1.0^(2,6)]-3-decen-8-ol (hydroxydicyclopentadiene) andcyclohexanol mean deuteration ratios at the positions denoted by thenumerals in each of the following chemical formulas. Further, in Table1, the isolation yields denoted by “-” mean that deuteration ratios weremeasured without isolating objective products after the TABLE 1deuteration. (2-Butanone)

(2-Norbornanone)

(Tricyclo[5.2.10^(2,6)]decan-8-one)

(Norborneol)

(Tricyclo[5.2.1.0^(2,6)]-3-decen-8-ol (or hydroxydicyclopentadiene)

(Cyclohexanol)

Reaction Isolation Deuteration Substrate Catalyst Temperature Yield (%)Ratio (%) Example 3 2-Butanone Pd/C 110° C. — (1) 92, (2) 80 Example 42-Heptanone Pd/C 160° C. 30 97 Example 5 3-Heptanone Pd/C 160° C. 32 97Example 6 Cyclohexanone Pd/C 180° C. 40 95 Example 7 2-Norbornanone Pd/C180° .C 90 (1) 43, (2) 99, Others 27 Example 8 Tricyclo[5.2.1.0^(2.6)]Pd/C 180° C. 88 (1) 20, (2) 40, decan-8-one (3) 99, Others 10 Example 9Sodium acetate Pd/C 160° C. 100 50 Example 10 Isobutylic acid Pd/C 160°C. — 40 Example 11 2-Heptanol Pd/C 160° C. 44 96 Example 12 4-HeptanolPd/C 160° C. 32 87 Example 13 Norborneol Pd/C 180° C. 32 (1) 38, (2) 72,(3) 66, (4) 28, Others 47 Example 14 Tricyclo[5.2.1.0^(2,6)]- Pd/C 180°C. 86 (1) 50, Others 25 3-decen-8-ol Example 15 Cyclohexanol Pd/C 180°C. 66 (1) 67, Others 77

Example 16

In 17 mL of deuterium oxide were suspended 500 mg oftricyclo[5.2.1.0^(2,6)]decan-8-ol (substrate) and 50 mg of palladiumcarbon, followed by replacing atmosphere of a sealed reaction systemwith hydrogen gas and conducting a reaction in an oil bath at 180° C.for about 24 hours. After completion of the reaction, the reactionsolution was extracted with ether, followed by filtering off thecatalyst and concentration of the filtrate under reduced pressure toobtain a product, which was subjected to structural analysis by ¹H-NMR,²H-NMR and mass spectrum measurements. Isolation yield and deuterationratio of the objective product was 60% and 45%, respectively. Resultsare shown in Table 2. In Table 2, amount of metal (% by weight) meansamount ratio of catalyst metal present in a carrier-supported catalystrelative to amount of the substrate, and deuteration ratio in Table 2means an average deuteration ratio of the whole deuteratable hydrogenatoms, and provided that (1) means deuteration ratio at the positiondenoted by (1) in the following chemical formula and “others” meansaverage deuteration ratio at the other positions than (1).

Examples 17 to 26

Deuteration of tricyclo[5.2.1.0^(2,6)]decan-8-ol was carried out in thesame manner as in Example 16 except for using catalysts shown in Table 2in amounts shown in Table 2 and reacting for reaction times shown inTable 2. Results are shown together in Table 2. TABLE 2 Isola- tionDeutera- Catalyst and Amount of Reaction Yield tion Amount thereof MetalTime (%) Ratio (%) Exam- Pd/C, 50 mg 1% by weight 24 hours 60 45 ple 16Exam- Pt/C, 100 mg 1% by weight 24 hours 36 61 ple 17 Exam- Pt/C, 100 mg1% by weight 48 hours 36 74 ple 18 Exam- Ru/C, 100 mg 1% by weight 24hours 53 (1) 100, ple 19 Others 15 Exam- Rh/C, 100 mg 1% by weight 24hours 58 (1) 51, ple 20 Others 32 Exam- Pd/C, 200 mg 4% by weight 24hours 40 70 ple 21 Exam- Pd/C, 250 md 5% by weight 24 hours 50 75 ple 22Exam- Pd/C, 250 mg 5% by weight 48 hours 23 87 ple 23 Exam- Pd/C, 50 mg2% by weight 24 hours 44 78 ple 24 Pt/C, 100 mg Exam- Pd/C, 100 mg 4% byweight 24 hours 41 (1) 96, ple 25 Pt/C, 200 mg Others 88

Example 26

In 17 mL of deuterium oxide, was suspended palladium carbon, followed byreplacing atmosphere of a reaction system with a hydrogen gas and thenstirring at room temperature for 3 hours to activate the palladiumcarbon. After completion of the activation, 500 mg of sodiummethacrylate (substrate) was charged thereto, followed by replacingatmosphere of the reaction system with nitrogen gas and conducting areaction in an oil bath at 180° C. for about 24 hours. After completionof the reaction, the reaction solution was filtered to remove thecatalyst, followed by concentration under reduced pressure to obtain acompound, which was subjected to structural analysis by ¹H-NMR and²H-NMR measurements. Isolation yield and deuteration ratio of thesubstrate were 100% and not less than 99%, respectively.

Examples 27 to 32

The same deuteration reactions as in Example 26 were conducted, exceptfor using substrates as deuteration targets and catalysts, shown in thefollowing Table 3 and conducting at each reaction temperature shown inTable 3. Isolation yields and deuteration ratios of thus obtainedcompounds are shown together in Table 3. In Table 3, isolation yielddenoted by “-” means the same as in Table 1. TABLE 3 Isola- Reactiontion Temper- Yield Deuteration Substrate Catalyst ature (%) Ratio (%)Example 26 Sodium Pd/C 180° C. 100   99≦ methacrylate Example 27 SodiumRh/C 160° C. 100 98 methacrylate Example 28 Sodium Rh/ 160° C. 100 98methacrylate alumina Example 29 Sodium Pt/C 180° C. 100 75 methacrylateExample 30 Sodium Raney- 160° C. 100 52 methacrylate Ni Example 31Sodium Ru/C 160° C. 100 23 methacrylate Example 32 Methacrylic Pd/C 180°C. — 90 acid

Comparative Example 1

The same deuteration reaction as in Example 26 was conducted, except forusing methacrylic acid as a substrate and non-activated palladium carbonas a catalyst, and the obtained compound was subjected to structuralanalysis by ¹H-NMR, ²H-NMR measurements. Deuteration ratio of thesubstrate was 75%.

Comparative Example 2

The same deuteration reaction as in Example 26 was conducted, except forusing methacrylic acid as a substrate and heavy hydrogen gas as a heavyhydrogen source, and the obtained compound was subjected to structuralanalysis by ¹H-NMR, ²H-NMR measurements. It was confirmed that thecarbon-carbon double bond of methacrylic acid was reduced, thoughdeuteration was performed.

It is clear from the results of Examples 1 to 32 that a compound havinga carbonyl group or a hydroxyl group can be efficiently deuterated bythe method for deuteration of the present invention.

It is also clear from the results of Examples 1 to 25 that in the casewhere a compound not having a carbon-carbon double bond is deuterated,activation of a catalyst and a deuteration reaction can be efficientlycarried out simultaneously in a reaction system.

From the results of Examples 24 and 25, it is clear that deuteration canbe performed by using two or more kinds of catalysts in combination.

From the results of Example 24 wherein palladium carbon and platinumcarbon were used in combination, though total amount of the catalystmetals was as low as 2% by weight relative to a substrate, it is clearthat obviously higher deuteration ratio can be obtained in comparisonswith Examples 21 and 22 wherein a single catalyst of palladium carbonwas used and amount of the catalyst metal was comparatively as high as4% by weight or 5% by weight.

From comparison of the results of Examples 21 and 25, it is clear thatExample 25, wherein deuteration was carried out by using palladiumcarbon and platinum carbon in combination, can provide higherdeuteration ratio in comparison with Example 21 wherein deuteration wascarried out using only palladium carbon as a catalyst, though amount ofthe catalyst metal(s) in each Example was the same (4% by weight).

Further, from comparisons of the results of Examples 26 to 32 andComparative Example 2, it is clear that even when a carbonyl compound ora secondary alcohol containing a carbon-carbon double bond or triplebond is deuterated, only objective deuteration proceeds withoutreduction of said double or triple bond by the method for deuteration ofthe present invention.

Further, from comparison of the results of Example 32 and ComparativeExample 1, it is clear that the method for deuteration of the presentinvention, wherein an activated catalyst is used, gives higherdeuteration ratio in comparison with the case wherein a non-activatedcatalyst is used.

Still further, from the results of Examples 1 to 32, it is clear thatthe method for deuteration of the present invention can efficientlydeuterate without making a reaction solution under basic condition.

INDUSTRIAL APPLICABILITY

A method for deuteration (replacement by deuterium or tritium) of thepresent invention, which comprises reacting a compound represented bythe general formula [1] with a heavy hydrogen source in the co-presenceof an activated catalyst can significantly improve working environment,because the deuteration which has been conventionally carried out undersevere conditions such as basic condition can be carried out underneutral condition. Further, even when the compound represented by thegeneral formula [1] is one having a carbon-carbon double bond or triplebond, the method for deuteration of the present invention enables toefficiently carry out objective deuteration without reduction of saiddouble bond or triple bond.

1. A method for deuteration of a compound represented by the generalformula [1]:R¹—X—R²  [1]wherein, R¹ represents an alkyl group or an aralkyl group,which may have a carbon-carbon double bond and/or triple bond; R²represents an alkyl group which may have a carbon-carbon double bondand/or triple bond, an aryl group, an aralkyl group, an alkoxy group, anaryloxy group or a hydroxyl group; X represents a carbonyl group or ahydroxylmethylene group; R¹ and R² may form an alicyclic ring togetherwith a carbon atom contained in X; provided that R² represents an alkylgroup which may have a carbon-carbon double bond and/or triple bond, anaryl group or an aralkyl group when X is a hydroxylmethylene group,comprising reacting the compound represented by the general formula [1]with a heavy hydrogen source in the co-presence of an activated catalystselected from a palladium catalyst, a platinum catalyst, a rhodiumcatalyst, a ruthenium catalyst, a nickel catalyst and a cobalt catalyst.2. The method for deuteration according to claim 1, wherein X is acarbonyl group in the general formula [1].
 3. The method for deuterationaccording to claim 1, wherein X is a hydroxymethylene group in thegeneral formula [1].
 4. The method for deuteration according to claim 1,wherein the heavy hydrogen source is a deuterated solvent.
 5. The methodfor deuteration according to claim 4, wherein the deuterated solvent isdeuterium oxide (D₂O).
 6. The method for deuteration according to claim1, wherein the activated catalyst selected from a palladium catalyst, aplatinum catalyst, a rhodium catalyst, a ruthenium catalyst, a nickelcatalyst and a cobalt catalyst is one obtained by activating anon-activated catalyst selected from a palladium catalyst, a platinumcatalyst, a rhodium catalyst, a ruthenium catalyst, a nickel catalystand a cobalt catalyst by contacting with hydrogen gas or heavy hydrogengas.
 7. The method for deuteration according to claim 6, wherein thecontact of a non-activated catalyst selected from a palladium catalyst,a platinum catalyst, a rhodium catalyst, a ruthenium catalyst, a nickelcatalyst and a cobalt catalyst with hydrogen gas or heavy hydrogen gasis conducted in a deuteration reaction system.
 8. The method fordeuteration according to claim 1, wherein the activated catalystselected from a palladium catalyst, a platinum catalyst, a rhodiumcatalyst, a ruthenium catalyst, a nickel catalyst and a cobalt catalystis a catalyst comprising an activated palladium based catalyst.
 9. Themethod for deuteration according to claim 8, wherein the activatedpalladium based catalyst is an activated palladium carbon.
 10. Themethod for deuteration according to claim 8, wherein the catalystcomprising an activated palladium based catalyst is a catalystcomprising an activated palladium catalyst and an activated platinumcatalyst.
 11. The method for deuteration according to claim 1, whereinthe compound represented by the general formula [1] istricyclo[5.2.1.0^(2,6)]decan-8-ol, and the activated catalyst selectedfrom a palladium catalyst, a platinum catalyst, a rhodium catalyst, aruthenium catalyst, a nickel catalyst and a cobalt catalyst is acatalyst comprising palladium carbon and platinum carbon. 12.Tricyclo[5.2.1.0^(2,6)]decan-8-ol wherein deuteration ratio thereof is60% or more.